PICOT is a critical regulator of cardiac hypertrophy and cardiomyocyte contractility.
PICOT (PKC-interacting cousin of thioredoxin) was previously shown to inhibit the development of cardiac hypertrophy, concomitant with an increase in cardiomyocyte contractility. To explore the physiological function of PICOT in the hearts, we generated a PICOT-deficient mouse line by using a gene trap approach. PICOT(-/-) mice were embryonic lethal indicating that PICOT plays an essential role during embryogenesis, whereas PICOT(+/-) mice were viable with no apparent morphological defects. The PICOT protein levels were reduced by about 50% in the hearts of PICOT(+/-) mice. Significantly exacerbated cardiac hypertrophy was induced by pressure overload in PICOT(+/-) mice relative to that seen in wild type littermates. In line with this observation, calcineurin-NFAT signaling was greatly enhanced by pressure overload in the hearts of PICOT(+/-) mice. Cardiomyocytes from PICOT(+/-) mice exhibited significantly reduced contractility, which may be due in part to hypophosphorylation of phospholamban and reduced SERCA activity. These data indicate that the precise PICOT protein level significantly affects the process of cardiac hypertrophy and cardiomyocyte contractility. We suggest that PICOT plays as a critical negative regulator of cardiac hypertrophy and a positive inotropic regulator.
Cha
Hyeseon
H
Global Research Laboratory and Department of Life Science, Gwangju Institute of Science and Technology, Buk-Gu, Gwangju, South Korea. hscha@gist.ac.kr
Kim
Ji Myoung
JM
Oh
Jae Gyun
JG
Jeong
Moon Hee
MH
Park
Chang Sik
CS
Park
Jaeho
J
Jeong
Hyeon Joo
HJ
Park
Byung Keon
BK
Lee
Young-Hoon
YH
Jeong
Dongtak
D
Yang
Dong Kwon
DK
Bernecker
Oliver Y
OY
Kim
Do Han
DH
Hajjar
Roger J
RJ
Park
Woo Jin
WJ
D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006321:Heart / Q000196:embryology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D011490:Protein Disulfide Reductase (Glutathione); D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D011490:Protein Disulfide Reductase (Glutathione); D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C498606:Txnl2 protein, mouse